An inflammatory response occurs when a tissue (cell) is injured or infected by foreign infectious agents (bacteria, fungi, viruses, or various allergens). It involves a series of complex physiological responses, including enzymatic activation, secretion of inflammation mediators, infiltration of body fluid, cell migration, and tissue damage, which are associated with various inflammation mediators and immunocytes in local blood vessels and body fluid. It also involves external symptoms such as erythema, edema, pyrexia and pain. Specifically, when external bacteria infiltrate a specific tissue and proliferate therein, leukocytes in the body recognize and actively attack the proliferated external bacteria. Dead leukocytes caused during this process are accumulated in the tissue infected by the bacteria while cells of the infiltrated bacteria killed by leukocytes are lysed in the tissue, resulting in formation of abscesses.
In the case of normal persons, inflammatory responses act to remove foreign infectious agents and regenerate injured tissue to restore the functions of the body. However, when an antigen is not removed or inflammatory responses occur excessively or continuously due to intrinsic substances, inflammatory responses cause life threatening diseases, including acute inflammation, joint diseases such as rheumatoid arthritis, skin diseases such as psoriasis, and allergic inflammatory diseases such as bronchial asthma, and also act as obstacles to treatment processes such as blood transfusion, drug administration and organ transplantation.
With recent developments in molecular biology, understanding of inflammatory diseases at the level of cytokine molecules has been attempted, and factors that influence such diseases have been identified one by one. Among such factors, nitric oxide (NO), an inflammatory mediator, acts to maintain homeostasis by performing a defensive function that damages pathogenic DNA (Kou and Schroder, Annuals of Surgery 221, 220-235, 1995).
NO is produced from L-arginine by three major nitric oxide synthase (NOS) isomers: nNOS (neuronal NOS), eNOS (endothelial NOS), and iNOS (inducible NOS). nNOS and eNOS are regulated by Ca2+/calmodulin, but iNOS is regulated at the transcriptional level by inflammatory stimuli such as interleukin, interferon and LPS. As is known in the art, NO produced in small amounts by nNOS or eNOS plays a role in normal physiological functions such as vasodilation, neurotransmission, and cell lysis against pathogens, but NO produced in excessive amounts by iNOS in macrophages is involved in a variety of pathophysiological processes including inflammation and cancer and reacts with superoxide to form peroxynitrite, which acts as a potent oxidant that damages cells and activates NF-B in macrophages activated by inflammatory stimuli, resulting in inflammatory responses and chronic diseases such as cancer and arteriosclerosis (Lawrence et al., Nat Med., 7:1291-1297, 2001).
Prostaglandin E2 (PGE2) and leukotriene are also inflammatory mediators that are produced from arachidonic acid. Particularly, PGE2 is produced by cyclooxygenase-2 (COX-2) enzyme and is produced mainly in macrophages and monocytes.
Asthma is a chronic inflammatory disease that is caused in the airway or lung by complex immune responses. It shows clinical symptoms, including wheezing caused by constriction of the airway due to various stimuli, difficulty in breading, and coughing, and can get better alleviated naturally or by treatment. Most asthmas are allergic diseases that frequently occur today, and show, in addition to chronic airway inflammation, airway obstruction symptoms caused by formation of allergen-specific immunoglobulin E (IgE) antibody, excessive secretion of airway mucus, or airway hypersensitivity.
Asthmas can be classified into extrinsic asthma and intrinsic asthma according to their cause. The term “extrinsic asthma” refers to asthma whose symptoms appear upon exposure to a causative antigen. It usually shows a positive response to a skin test or bronchial provocation test against the causative antigen and generally occurs in a young age group. House dust and mites are the most frequent causative antigens, and in addition, pollens, animal epithelium, molds also act as the causative antigens. Intrinsic asthma is caused or becomes worse by upper airway infection, exercise, emotional unrest, cold climate and humidity change and can be frequently seen in an adult group. In addition, there are drug-induced asthma, exercise-induced asthma, and occupational asthma.
Considering the rapid increase in allergic diseases in the past 30 years, it has been strongly suggested that asthma is caused mainly by extrinsic factors rather than intrinsic factors such as genetic factors. Among such extrinsic factors, the change in the immune system of the body by an external environment is most predominant. Particularly, asthma is recognized as a chronic inflammatory disease that is caused by the proliferation, differentiation and activation of inflammatory cells by interleukin-4, interleukin-5 or interleukin-13, which is produced in TH2 (T helper 2) type immune cells by allergens, and the migration and infiltration of the inflammatory cells into the airway and tissue surrounding the airway (Elias J A, et al., J. Clin. Invest., 111, pp 291-297, 2003). In this case, inflammatory cells, including activated eosinophils, mast cells and alveolar macrophages, secrete various inflammatory mediators (cysteine leukotrienes, prostaglandins, etc.) while strong constriction of bronchi plays an important role in the process (Maggi E., Immunotechnology, 3, pp 233-244, 1998; Pawankar R., Curr. Opin. Allergy Clin. Immunol., 1, pp 3-6, 2001; Barnes P J, et al., Pharmacol Rev., 50, pp 515-596, 1998).
Until now, a variety of therapeutic agents have been commonly used, but a considerable number of therapeutic agents should be used with care, because they can cause side effects. At present, inhaled corticosteroid formulations are most frequently used as therapeutic agents and show excellent effects. However, it is known that, when these formulations are used for a long period of time, they cause adrenal gland inhibition, a decrease in bone density, growth disorders, complications of eyes and skin, in proportion to the dose and time of use thereof. In addition, it was reported that the corticosteroid formulations can increase the synthesis of collagen (Warshmana G S, et al. Dexamethasone activates expression of the PDGF-alpha receptor and induces lung fibroblast proliferation. Am J Physiol 274, 499-507, 1998). For these reasons, even though the treatment of chronic asthma patients with corticosteroids has been performed for several years, asthma patients in which airway hypersensitivity was suppressed to a normal state were rare. Moreover, it is known that long-term administration of a beta-2 agonist does not suppress the reconstitution of the airway (Jeffery P K, et al. Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study. Am Rev Respir Dis 145: 890-0, 1992). In addition, it was reported that long-lasting beta-2 agonists such as salmeterol and formeterol can cause the death of asthma patients, even though they can prevent asthma attacks. Although various side effects as described above have been reported, these agents have been continuously prescribed under the judgment that the effect of alleviating asthma symptoms is greater than the risk of side effects. However, the results of measuring the growth rate of child asthma patients indicated that the growth rate of child asthma patients administered with an oral leukotriene antagonist (montelukast) was higher by up to 1 cm per year than that of child asthma patients administered with an inhaled corticosteroid formulation (Garcia Garcia M L, et al. Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year old patients with mild asthma: the MOSAIC study. Pediatrics 116 (2): 360-9, 2005). When asthma in the growth phase is not controlled, the growth of not only the lungs, but also other parts of the body, can be inhibited. For this reason, it is essential for growth to maintain normal lung functions by continuous treatment. However, because it is particularly important to use a safe drug for continuous treatment and sufficiently control inflammation of the airway, side effects together with asthma alleviating effects should be carefully considered in the selection of therapeutic agents.
Thus, there has been a need for the development of drugs which have excellent immunotherapeutic and anti-inflammatory effects and cause little or no side effects, and thus can be safely used for a long period of time. For this reason, studies on the development of materials from natural resources through verifications of the effects thereof have been activated.
Meanwhile, the genus Lagerstroemia includes about 50 kinds of plants. Among them, Lagerstroemia indica L. is known to have the effects of stopping bleeding and removing tumors, and is known to be effective against metrorrhagia, leukorrhea with reddish discharge, traumatic bleeding, enteritis, diarrhea and the like. An extract of Lagerstroemia indica L. and the active ingredient thereof are known to have anti-allergic effects (Korean Patent Laid-Open Publication No. 10-2011-0050938). In addition, Lagerstroemia speciosa is effective against diabetes and obesity, and a Lagerstroemia speciosa leaf extract is known to have an antioxidant effect (Japanese Patent Laid-Open Publication No. 1998-291935). However, the anti-inflammatory activity or anti-asthma activity of Lagerstroemia ovalifolia among plants belonging to the genus Lagerstroemia has not yet been known.